The elderly have a high prevalence (10-20%) of vitamin B12 (cobalamin) deficiency, but the clinical consequences of this deficiency are still unknown. Elevated serum methylmalonic acid and total homocysteine are the most sensitive and specific measures of clinical deficiency. Hyperhomocysteinemia has been found to be an independent risk factor for vascular disease in younger populations. A major objective of this proposal is to determine whether hyperhomocysteinemia due to cobalamin deficiency is correlated with cardiovascular disease in a large ethnically diverse female elderly population from the Women's Health and Aging Study. It will also be determined whether cobalamin deficiency with elevated methylmalonic acid and/or total homocysteine levels causes megaloblastic anemia and/or disorders of vibration sense and balance. The effect of standard multivitamin use will be determined on the prevalence of cobalamin or folate deficiency or elevated metabolites. The interaction between cobalamin status and a common polymorphism for thermolabile methylenetetrahydrofolate reductase will be studied in an elderly outpatient population, in cobalamin deficient subjects with neurologic disease or those with extremely high levels of homocysteine and megaloblastic anemia. It will also be determined whether the homozygous thermolabile mutations cause an abnormal post methionine load homocysteine level. Polymerase chain reaction based methods will be used to genotype subjects and stable isotope dilution gas chromatography-mass spectrometry assays will be used to quantitate methylmalonic acid and total homocysteine. After the food folate fortification program is fully implemented in 1998, millions of elderly Americans with previously untreated cobalamin deficiency will be exposed to folate fortified food. This proposal seeks to investigate the clinical consequences of cobalamin deficiency in the elderly in order to improve diagnosis and replacement therapy for these individuals.